Jill Fiedler-Kelly

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation

A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy.

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18–64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme‐inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in nonwhites and increased by 13% in patients receiving more than one concomitant enzyme‐inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme‐inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme‐inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel

Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. Experimental Design: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m2). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. Results: The MTD of LEP-ETU was identified as 325 mg/m2. DLTs occurring at 375 mg/m2 consisted of febrile neutropenia and neuropathy. The Cmax and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 μg/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m2 q3w. For a dose of 110 mg/m2 given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. Conclusions: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m2 LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m2 Taxol q3w. A 275 mg/m2 dose may offer an improved therapeutic index.

Prospective Use of Population Pharmacokinetics/ Pharmacodynamics in the Development of Cisatracurium

AbstractPurpose. The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. Methods. Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I−III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. Results. The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. Conclusions. The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

Impact of Triplicate Prescription Program on Psychotropic Prescribing Patterns in Long-Term Care Facilities

OBJECTIVE: To assess the impact of the effect of the New York state triplicate prescription program on psychotropic prescribing patterns in selected long-term care facilities over a one-year period. DESIGN: Retrospective study for changes in psychotropic drug use patterns before and after implementation of the triplicate prescription program. SETTING: Eight private and two public long-term care facilities in the western New York area. PATIENTS: All residents in the long-term care facilities with complete medical records for a one-year period were reviewed. OUTCOME MEASUREMENTS: Charts were reviewed for changes in psychotropic drug patterns and incidence in adverse events such as falls, hip fractures, hospital admission, signs or symptoms of benzodiazepine (BZD) withdrawal syndrome, or behavioral outburst. MAIN RESULTS: BZD use declined precipitously from 25 percent of psychotropic drug orders to 10 percent six months after implementation of the program. The decline in BZD use was accompanied by an increase in the number of orders for alternative psychotropic agents. Although 22 percent of the patients previously receiving BZDs were discontinued from these drugs, more than half of these patients were switched to alternative therapy, including tricyclic antidepressants and antipsychotic drugs. The majority of patients who discontinued BZDs did so without tapering of the dosage; however, few experienced minor withdrawal symptoms and no patient experienced seizures or required hospitalization following discontinuation. The risk of falls, hospital admission for any reason, or combined events was not significantly altered despite a reduction in BZD use. There was a trend, however, for a reduction in falls after implementation of the program. CONCLUSIONS: This study documents that psychotropic drug prescribing patterns were significantly affected by the triplicate prescription program. BZD use declined; however, use of alternative psychotropic drugs increased. Despite changes in psychotropic prescribing patterns, we found no significant risk of adverse events. Further study to evaluate the long-term effect of alternative psychotropic drugs is necessary.

Challenges in the Transition to Model-Based Development

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle, to the successful transition to model-based drug development. Challenges with timely data availability, high data discard rates, delays in completing modeling and simulation activities, and resistance of development teams to the use of modeling and simulation in decision making are all symptoms of an immature process capability for performing modeling and simulation.A process that will fulfill the promise of model-based development will require the development and deployment of three critical elements. The first is the infrastructure—the data definitions and assembly processes that will allow efficient pooling of data across trials and development programs. The second is the process itself—developing guidelines for deciding when and where modeling and simulation should be applied and the criteria for assessing performance and impact. The third element concerns the organization and culture—the establishment of truly integrated, multidisciplinary, and multiorganizational development teams trained in the use of modeling and simulation in decision-making. Creating these capabilities, infrastructure, and incentivizations are critical to realizing the full value of modeling and simulation in drug development.

Dose Proportionality of Cisatracurium

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration—time data from 131 patients with limited concentration—time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed‐effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.

Population pharmacokinetics of tirilazad: effects of weight, gender, concomitant phenytoin, and subarachnoid hemorrhage.

AbstractPurpose. Data collected during Phase I and II in the development of tirilazad were pooled and analyzed using nonlinear mixed effects models to assess covariates which might affect tirilazad pharmacokinetics. Methods. Four single dose and five multiple dose studies in normal volunteers were combined with two multiple dose studies performed in patients with subarachnoid hemorrhage (SAH) to identify factors related to intersubject variability in clearance (CL) and central compartment volume (Vc). Data from 253 subjects, which consisted of 7,219 tirilazad concentrations, were analyzed. The effects of weight, gender, patient versus volunteer status, and phenytoin use were evaluated. Results. Relative to male volunteers not receiving concomitant phenytoin, significant effects on clearance included: a 46% increase in volunteers receiving phenytoin, and an 82% increase in clearance associated with SAH patients (all of whom received phenytoin). Significant effects on Vc were: a 26% increase for female volunteers not receiving phenytoin, a 12% decrease for volunteers receiving concomitant phenytoin, a 152% increase for male SAH patients, and a 270% increase for female SAH patients. Incorporating patient covariate effects substantially reduced the interindividual variability (from 27.9% to 24.7% for clearance and from 48.2% to 37.5% for Vc). Residual variability was estimated at 66% coefficient of variation (CV) in SAH patients and at 22−48% CV over the range of predicted concentrations in normal volunteers. Conclusions. The most important factors affecting tirilazad pharmacokinetics are the administration of phenytoin (increased CL) and SAH (increased Vc and residual variability). The effect of gender on tirilazad pharmacokinetics was modest.

An Automated Drug Concentration Screening and Quality Assurance Program for Clinical Trials

The collection and analysis of drug concentration data collected during clinical trials is growing in popularity as a mechanism for explaining variability in patient outcomes. This paper describes an automated drug concentration screening and quality assurance program to monitor the acquisition of drug dosing information and concentration time data during clinical trials. This program serves to expedite the data cleaning process, allows for monitoring of possible concentration-related safety events, screens for drug-drug interactions during the execution of clinical trials, and provides the ability to produce interim, blinded reports to the sponsor and the data safety monitoring board. The goal of this paper is to describe the operation of the program as it has been used in practice and to highlight its benefits in the development program for delavirdine mesylate, a nonnucleoside reverse transcriptase inhibitor recently approved for the treatment of HIV infection.

Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models: Owen/Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models

This book provides a user-friendly, hands-on introduction to the Nonlinear Mixed Effects Modeling (NONMEM) system, the most powerful tool for pharmacokinetic / Cwers conditional weighted least in each individual clearances of collinearity. Statistical model describing noise rather than articles and individual. A given by hearing lectures for unexplainable random effects as a requirement relevant. Qq quantilequantile qq plots of quantification lloq pharmacokinetic pharmacodynamic analysis evaluating. Body build basic principles and type are not deviate. Eq jill fiedler kelly is, not physically entering. Population parameters are available at ecog, and individual subjects generally need.